The proposed Program Project Grant (PPG), New Molecules in Triglyceride Metabolism and Adipogenesis, is guided by a common objective-to study mechanisms for triglyceride delivery to peripheral tissues and to define new mechanisms in adipogenesis. This PPG is highly relevant to obesity and hyperlipidemia, two public health problems that are central to the mission of the NHLBI. During the past year, the project and core leaders of this PPG have uncovered new molecules regulating plasma lipid metabolism, fuel delivery to cells, and adipogenesis. Although these novel molecules and targets were discovered by diverse experimental approaches, they all are directly connected to lipogenesis and to PPARy (peroxisome proliferator-activated receptor gamma), a key regulator of adipogenesis and triglyceride metabolism. The convergence of intellectual interests around a single topic, triglyceride metabolism and adipogenesis, has fueled our collaborative interactions, which in turn have led to entirely new discoveries. This PPG is organized into three projects and two cores. Project 1, Function and Regulation of GPIHBP1 in Lipid Metabolism, will be led by Dr. Stephen G. Young. This project will deal with a novel endothelial cell protein, GPIHBP1 (glycosylphosphatidylinositol-anchored high density lipoprotein-binding protein 1), which is critically important for the lipolytic processing of triglyceride-rich lipoproteins and for the delivery of lipid nutrients to adipose tissue, heart, and skeletal muscle. Project 2, The Lipin Protein Family and Triglyceride Metabolism, will be led by Dr. Karen Reue. Dr. Reue's identification of the mutation causing fatty liver dystrophy led to the discovery of the lipin family of proteins, which have key roles in adipogenesis and triglyceride synthesis. The lipin proteins are intriguing because they function as triglyceride biosynthetic enzymes as well as transcriptional coactivators. Project 3, Novel Pathways for Triglyceride Storage and Adipogenesis, will be led by Dr. Peter Tontonoz. Using a novel high-throughput screening approach, Dr. Tontonoz has identified entirely new cDNAs involved in adipogenesis, as well as small-molecule regulators of adipogenesis. Dr. Tontonoz is poised to elucidate these new players in the field of triglyceride metabolism and adipogenesis. A Mouse Model and Antibody Core (Core A) will create new genetically modified mice and polyclonal and monoclonal antibody reagents for the three projects. An Administration Core (Core B) will support the personnel of each project, organize advisory board meetings, and ensure compliance with institutional and NIH guidelines.